Method and apparatus for in-vivo transdermal and/or intradermal delivery of drugs by sonoporation

ABSTRACT

An apparatus for performing in-vivo sonoporation of a skin area and transdermal and/or intradermal delivery of a drug solution includes a container having an end adjacent the skin area and containing the drug solution. The container further includes an ultrasound horn having a tip submerged in the drug solution for applying ultrasound radiation to the drug solution. The ultrasound radiation has a frequency in the range of 15 KHz and 1 MHz and is applied at an intensity, for a period of time and at a distance from said skin area effective to generate cavitation bubbles. The cavitation bubbles collapse and transfer their energy into the skin area, thus causing the formation of pores in the skin area. The ultrasound radiation intensity and distance from the skin area are also effective in generating ultrasonic jets, which ultrasonic jets then drive the drug solution through the end adjacent the skin area and the formed pores into the skin.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.09/690,604, filed Oct. 17, 2000, scheduled to issue Nov. 26, 2002, asU.S Pat. No. 6,487,447, the entire disclosure of which is incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to a method and an apparatus fortransdermal and/or intradermal delivery of drugs by sonoporation andmore particularly to in-vivo transdermal and/or intradermal delivery ofdrugs.

BACKGROUND OF THE INVENTION

Transdermal and/or intradermal delivery of drugs offer severaladvantages over conventional delivery methods including oral andinjection methods. It delivers a predetermined drug dose to a localizedarea with a controlled steady rate and uniform distribution, isnon-invasive, convenient and painless.

Transdermal and/or intradermal delivery of drugs require transport ofthe drug molecules through the stratum corneum, i.e., the outermostlayer of the skin. The stratum corneum (SC) provides a formidablechemical barrier to any chemical entering the body and only smallmolecules having a molecular weight of less than 500 Da (Daltons) canpassively diffuse through the skin at rates resulting in therapeuticeffects. A Dalton is defined as a unit of mass equal to {fraction(1/12)} the mass of a carbon-12 atom, according to “Steadman'sElectronic Medical Dictionary” published by Williams and Wilkins (1996).

In co-pending patent application entitled “Method of forming microporesin skin”, incorporated herein by reference, sonoporation has beenproposed as a method to facilitate transdermal and/or intradermaldelivery of molecules larger than 500 Da and to increase the rate ofdrug delivery through the SC. The sonoporation apparatus described inthe referenced application is not practical for in-vivo drug deliveryand in particular for treating humans.

It would be advantageous to provide a method and an apparatus forin-vivo transdermal and/or intradermal delivery of any size drugmolecules.

SUMMARY OF THE INVENTION

In general, in one aspect, the invention provides an apparatus forperforming in-vivo sonoporation of a skin area and transdermal and/orintradermal delivery of a drug solution including a container having anend covered with a porous membrane and containing the drug solution andan ultrasound horn having a tip submerged in the drug solution. Theultrasound horn applies ultrasound radiation to the drug solution. Theultrasound radiation has a frequency in the range of 15 KHz and 1 MHzand is applied at an intensity, for a period of time and at a distancefrom said skin area effective to generate cavitation bubbles. Thecavitation bubbles collapse and transfer their energy into the skin areathus causing the formation of pores in the skin area. The ultrasoundradiation intensity and distance from the skin area are also effectivein generating ultrasonic jets, which ultrasonic jets then drive the drugsolution through the porous membrane and the formed pores into the skinarea.

Implementations of the invention may include one or more of thefollowing features. The membrane may have pores with a diameter of 100micrometers. The membrane may be hydrophobic. The tip may be removableconnected to the ultrasound horn and it may have a distal end surface,which is flat or concave. The distal end surface may have a plurality ofdepressions. The tip may also have a body having markings indicating theamount of the drug solution contained in the container. A removableprotective film may cover the membrane. The container may have an outerwall, an inner wall and an absorbent wick placed between the inner andouter wall. The wick absorbs any excess drug solution that is not driveninto the skin area through the formed pores and it may be made of highlyabsorbent and hydrophilic material such as absorbent cellulose material,polyvinyl alcohol sponge, Sodium Carboxy-Methyl Cellulose (CMC),blotting paper and any other spongy materials.

The container inner wall may have first and second grooves and tip mayhave a body having first and second grooves. The tip is inserted intothe container and placed so that the first and second grooves of the tipbody are opposite the first and second grooves of the container innerwall. This arrangement defines first and second spaces for accommodatingfirst and second o-rings, respectively. The container may also have aninlet septum for filling it with the solution. The container may be acylinder made of a transparent material and/or plastic material.

The ultrasound frequency may be 20 KHz and the ultrasound intensity maybe in the range of 5 W/cm² and 55 W/cm². The tip may have a distal endlocated at a distance from the membrane in the range of 1 millimeter to10 millimeters. The ultrasound radiation may be continuous or pulsed andit may be applied for a period of time in the range of about 30 secondsto 5 minutes, preferably 1 minute for continuous exposure or about 10minutes to 20 minutes for pulsed exposure with a 5% duty cycle,respectively. The formed pores may have a diameter in the range of 1micrometer to 100 micrometers.

In general, in another aspect, the invention features a method ofperforming in-vivo sonoporation of a skin area and transdermal and/orintradermal delivery of a drug solution. The method includes providing acontainer containing a predetermined amount of the drug solution andhaving a first end and a second end, the second end being covered with aporous membrane. Next a tip of an ultrasound horn is submerged in thedrug solution through the first end of the container and then the porousmembrane is placed in contact with the skin area. The ultrasoundradiation is then turned on having a frequency in the range of 15 KHzand 1 MHz. The ultrasound radiation is applied with an intensity, for aperiod of time and at a distance from the skin area effective togenerate cavitation bubbles. The cavitation bubbles collapse andtransfer their energy into the skin area thus causing the formation ofpores in the skin area. The ultrasound radiation intensity and distancefrom the skin area are also effective in generating ultrasonic jets,which ultrasonic jets then drive the drug solution through the porousmembrane and the formed pores into the skin area.

Among the advantages of this invention may be one or more of thefollowing. The apparatus allows a painless and rapid delivery of drugsthrough the skin for either topical or systemic therapy. The apparatusallows coupling of the ultrasound radiation to a container containingthe drug solution without dampening the ultrasound intensity.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and description below. Other features, objectsand advantages of the invention will be apparent from the followingdescription of the preferred embodiments, the drawings and from theclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of in-vivo transdermal and/orintradermal delivery of an anti-inflammatory drug via an ultrasonicapparatus.

FIG. 2 is a graph depicting a pulsed ultrasound wave.

FIG. 3 is a cross-sectional side view of an ultrasonic drug deliveryapparatus.

FIG. 4 is a side view of an ultrasonic horn tip with a flat surface tiparea.

FIG. 5 is a side view of an ultrasonic horn tip with a concave surfacetip area

FIG. 6A side view of an ultrasonic horn tip with a tip surface havingdepressions.

FIG. 6B is bottom view of the tip surface of FIG. 6A having depressions.

FIG. 7 is a cross-sectional side view of an ultrasonic drug deliveryapplicator.

FIG. 7A is a cross-sectional side view of the porous hydrophobicmembrane 250.

FIG. 8 is a flow diagram of an in-vivo transdermal and/or intradermaldrug delivery method.

Like reference numbers and designations in the various drawings indicatelike elements.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Referring to FIG. 1, an ultrasonic transdermal and/or intradermal drugdelivery apparatus 10 is used to deliver an anti-inflammatory drug to askin area 20 of a patient's face 30, which is affected with acne. Theultrasonic drug delivery apparatus 10 includes an applicator 200 thatcontains the liquid based anti-inflammatory drug and an ultrasonictransducer 100. Ultrasonic transducer 100 generates ultrasound waves,which then couple to the applicator 200 and ultimately to the patient'sface 30 through an ultrasonic horn 110. During the treatment, the bottomsurface 204 of the ultrasonic drug delivery applicator 200 is placed incontact with the affected skin area 20 and the ultrasound transducer 100is turned on for a predetermined time period. The generated ultrasoundwaves have a predetermined frequency, power and duty cycle. Theultrasound waves cause sonoporation of the skin, as described in theco-pending application entitled “Method of forming micropores in skin”incorporated herein by reference. Sonoporation generates micro-pores inthe skin area 20 and a predetermined amount of the anti-inflammatorydrug solution is painlessly transported through the micro-pores insidethe skin. This procedure is repeated as many times as necessary to coverthe total affected skin area and to deliver the total prescribed amountof the anti-inflammatory drug.

Referring to FIG. 2, in one example, the ultrasound waves are pulses 119having a frequency of 20 KHz and intensity 119 c of 20 W/cm². The pulsewidth 119 a is 0.5 seconds, the time interval 119 b between the end ofone pulse and the beginning of the next is 9.5 seconds and the period ofthe ultrasound wave is 10 seconds. In one example, the skin is exposedto ultrasound for 20 minutes with a 5% duty cycle (i.e., 120 pulses witheach pulse providing ultrasound energy for 0.5 seconds) resulting in atotal of 1 minute of continuous ultrasound exposure.

Referring to FIG. 3, ultrasonic horn 110 has a first end 112 connectedto the ultrasonic transducer 100 and a second end 114 attached to aremovable cylindrical tip 400. Ultrasonic transducer 100 connects via acable 102 to a power supply 150 that energizes the transducer 100. Thecylindrical tip 400 has a first end 402 with a threaded post 406 and asecond end 404. Threaded post 406 is screwed into threaded hole 120located at the second end 114 of the ultrasonic horn 110. Second end 404of the cylindrical tip 400 has markings 500 indicating the level of thedrug solution 300 contained in the applicator 200. Applicator 200includes a cylindrical container 205 with a first open end 203 and asecond end 204. Second end 204 is covered with a porous membrane 250.Membrane 250 has pores 252 with a diameter of a few micrometers, ahydrophobic, non-wettable inside surface 251 and an outside surface 254,shown in FIG. 7A. Outside surface 254 is covered with a removableprotective film 260 that keeps the drug solution 300 contained in thecylindrical applicator container 200. The ultrasonic horn tip 400 isinserted into the applicator container 200 through the first open end203. First and second O-rings, 210 and 220, respectively, keep theultrasonic horn tip 400 submerged in the drug solution 300 and preventleakage of the drug solution 300.

Referring to FIG. 4, the tip 400 of the ultrasonic horn 110 includes inaddition to the above mentioned threaded post 406 and markings 500, afirst groove 440 and a second groove 460 that accommodate first andsecond O-rings 210 and 220, respectively. In one example, the tip 400 ismade of titanium and has a length of 10 cm, and a diameter of 1 cm. Thebottom surface 410 of the tip 400 is flat and during the time thetransducer 100 is on it emits scattered ultrasound waves that causerandom micro-poration of the skin.

In other embodiments the emitted ultrasound waves are focused orparallel. Referring to FIG. 5, an ultrasonic horn tip 400 with a concavebottom surface 410 is used to generate ultrasound waves that focus overa very small skin area. Focused ultrasound waves are used for deep skinmicro-poration over a small skin area.

Referring to FIGS. 6A and 6B, an ultrasonic horn tip 400 with a bottomsurface 410 having concave depressions 411 is used to generate parallelultrasound waves. The overall form and direction of the ultrasound wavesdepends upon the shape, curvature radius, density and distribution ofthe depressions 411 across the bottom surface 410. In the embodiment ofFIG. 6B, depressions 411 have the same shape and curvature radius andare uniformly distributed across the bottom surface 410. In alternativeembodiments, the shape, curvature radius, density and distribution ofthe depressions are varied across the bottom surface 410. Parallelultrasound waves are used to generate uniform distribution ofmicro-pores on the skin surface.

Referring to FIG. 7, a drug delivery applicator 200 includes acylindrically shaped hollow container 205 that has an inner wall 201spaced apart from an outer wall 202 and a wick 270 situated in the spacebetween inner wall 201 and outer wall 202. The container 205 ispreferably made of a transparent hard plastic material and is discardedafter use. The wick 270 is made of a highly absorbent and hydrophilicmaterial. In one example, the wick 270 is made of a high-absorbencypolyvinyl alcohol sponge (PVA), manufactured by the M-Pact company underthe tradename of CLINICEL™. Other examples of highly absorbent andhydrophilic material include HYDROFERA™ PVA sponge manufactured byHydrofera LLC, Sodium Carboxy-Methyl Cellulose (CMC), blotting paper andany other spongy material. Both the inner and outer applicator walls201, 202 are basically cylindrical and axially aligned, with theexception of two locations on the inner surface 208 of the innerapplicator wall 201 where two grooves 212 and 214 are cut out. Grooves212 and 214 are aligned and placed opposite grooves 440 and 460 cut intothe outer surface 408 of the ultrasonic horn tip 400, respectively.O-rings 210 and 220 occupy the space formed between the oppositelyplaced grooves 212, 440 and 214, 460, respectively. O-rings 210 and 220facilitate a secure and leak proof fit of the ultrasonic horn tip 400into the drug delivery applicator 200.

Again with reference to FIG. 7, the drug solution inlet septum 230 islocated between the outer applicator wall 202 and the inner applicatorwall 201 approximately halfway between the open top 203 and bottomsurface 204 of the ultrasonic drug delivery applicator 200. The septum230 is constructed of a silicon rubber material, designed to beimpervious to liquids yet allow injection of the drug solution into theultrasonic drug delivery applicator 200 using a hypodermic needle.

Referring to FIG. 7A, porous membrane 250 is attached to the bottom 255of the inner applicator container wall 201. Membrane 250 is constructedof a hydrophobic material that resists the passage of the aqueous liquiddue to its non-wettable inner surface 251 and has pores 252 with adiameter in range of 10 to 100 micrometers, preferably with diameter of50 micrometers. In one example, membrane 250 is made of a non-wovenpolypropylene. The bottom surface 253 of membrane 250 is covered with aremovable protective film 260. In one example, the removable protectivefilm 260 is a thin plastic sheet that is attached to the membrane via asilicon based adhesive 254.

In operation, a sterilized ultrasonic drug delivery applicator 200 isplaced over the tip of ultrasonic horn 400. A predetermined drugsolution 300 is then introduced into the cylindrical applicatorcontainer 205 through the inlet septum 230 via a hypodermic needle (notshown). When the ultrasonic drug delivery applicator 200 is properlyfilled, the tip of the ultrasonic horn 400 is partially immersed in thesolution 300. Visual inspection of the solution level marking 500indicates whether the applicator is properly filled, and whether theultrasonic drug delivery applicator 200 is leaking or defective. Oncethe ultrasonic drug delivery applicator 200 is filled and determined tobe ready for use, the protective film 260 is peeled-off exposing theporous membrane 250. The apparatus 10 is then placed on the patient'sskin, oriented such that the porous membrane 250 is flush with the skinarea where the drugs are to be administered and such that the bottom ofthe horn tip 410 is immersed in drug solution 300. A timer (not shown),which is included in the power supply, is set to a pre-determined lengthof time for sonoporation. The power supply is switched on, and theapparatus sonoporates the skin for an allotted amount of time.

The membrane 250 resists passage of the aqueous drug solution 300 due toits non-wettable inside surface 251 and the small size diameter pores. Aquantity called the breakthrough pressure (P) is used to quantify thehydraulic pressure of the liquid drug that is needed to break throughthe porous membrane. The breakthrough pressure (P) is described by thefollowing mathematical formula:P=(−4γ cos ζ)/D  Equation 1Where:

γ is the surface tension of the liquid,

ζ is the contact angle formed between the liquid and the smooth surfaceof the membrane,

D is the effective pore diameter of the membrane

When the pressure of the drug solution is less than (−4γ cos ζ)/D, thedrug solution 300 remains contained inside the applicator container 205.In this case, the purpose of the porous membrane is to prevent the drugsolution from leaking prior to transdermal or intradermal infusionprocess while allowing the ultrasound waves to freely pass through andreach the skin surface 20 and to generate the micro-pores in the stratumcorneum. When the pressure of the drug solution 300 is higher than (−4γcos ζ)/D, the drug solution 300 passes through the membrane pores andreaches the skin surface 20, from where it is then transported via theultrasonic jet pressure through the skin micro-pores into the skin.Excess liquid transferred to the skin during the ultrasound exposure isabsorbed by the wicking action of wick 270. After use, the ultrasonicdrug delivery applicator 200 is removed form the ultrasound tip anddiscarded.

Referring to FIG. 8, a method 600 of transdermal and/or intradermal drugdelivery using the drug delivery applicator of the present inventionincludes the general steps of preparing the sonoporation apparatus foruse, verifying that it is functioning normally, exposing a patient'sskin to ultrasound and administering drugs.

In particular, in the preparation step, an operator first sterilizes 610the tip of the ultrasonic horn, then assembles 620 the ultrasonic horntip with the ultrasonic horn, then attaches 625 the ultrasonic drugdelivery applicator (UDDA) to the ultrasonic horn tip and finallyinjects 630 the drug solution into the UDDA.

The ultrasonic horn tip 400 may be sterilized using an ethylene oxidegas or by exposing the horn tip 400 to steam. The horn tip may also bepre-sterilized and sealed in a protective package. The sterilizedultrasonic horn tip 400 is attached to the ultrasonic horn 110 byscrewing the threaded post 406 of the tip 400 into the threaded hole 120of the ultrasonic horn 110. The UDDA is attached to the tip of theultrasonic horn 400 by inserting the device onto the tip 400, asdescribed in FIG. 7. The drug solution 300 is injected into theultrasonic drug delivery applicator 200 via the inlet septum 230 using asyringe.

In the function verification step 640 the operator compares the level ofthe drug solution 300 in the ultrasonic drug delivery applicator 200 tothe level marking 500 via a visual inspection. If the levels are alignedthe operator proceeds with the treatment by first removing theprotective film 260 from the ultrasonic drug delivery applicator 200,then orienting and placing 650 the apparatus on the patient's skin sothat the porous membrane is flush with the skin surface and the tip ofthe ultrasonic horn 400 is immersed in the drug solution 300.

Next the operator administers 670 the drug solution. For this purpose,the ultrasound power is turned on for a predetermined period of time,and ultrasound waves are generated having a frequency, power and dutycycle so that they cause formation of micro-pores in the skin andsubsequently transfer the drug from the ultrasonic drug deliveryapplicator 200 through the skin micro-pores and across the SC into theblood vessels of the blood capillary system. At the end of a successfultreatment the power supply is set to a stand-by condition and the UDDAis discarded 690.

If in the function verification step 640 the levels are not aligned, theoperator proceeds to check 660 via a visual inspection if there are anyleaks or defects in the UDDA. If there are no obvious sources of error,the operator adds 680 more drug solution to fill the UDDA to theappropriate level and then checks 640 again the levels. If the UDDAappears to be leaking or is otherwise defective, the operator discards690 the defective UDDA and repeats step 625.

The many features and advantages of the present invention are apparentfrom the detailed specification, and thus, it is intended by theappended claims to cover all such features and advantages of thedescribed apparatus that follow the true spirit and scope of theinvention. Furthermore, since numerous modifications and changes willreadily occur to those of skill in the art, it is not desired to limitthe invention to the exact construction and operation described herein.Moreover, the process and apparatus of the present invention, likerelated apparatus and processes used in medical applications tend to becomplex in nature and are often best practiced by empiricallydetermining the appropriate values of the operating parameters or byconducting computer simulations to arrive at a best design for a givenapplication. Accordingly, other embodiments are within the scope of thefollowing claims.

1. An apparatus for performing in-vivo sonoporation of skin area andtransdermal and/or intradermal delivery of a drug solution comprising:an ultrasound horn having a tip submerged in said drug solution andapplying ultrasound radiation to said drug solution wherein saidultrasound radiation has a frequency in the range of 15 KHz and 1 MHzand is applied at an intensity, for a period of time and at a distancefrom said skin area effective to generate cavitation bubbles, whereinsaid cavitation bubbles collapse and transfer their energy into the skinarea thus causing the formation of pores in the skin area; and whereinsaid ultrasound radiation intensity and distance from the skin area arealso effective in generating ultrasonic jets, said ultrasonic jetsdriving said drug solution transdermally through said formed pores intothe skin area.
 2. The apparatus of 1 wherein said formed pores have adiameter in the range of 1 micrometer to 100 micrometers.
 3. Theapparatus of 1 wherein said tip is removably connected to saidultrasound horn.
 4. The apparatus of 1 wherein said tip comprises a flatdistal end surface.
 5. The apparatus of 1 wherein said tip comprises aconcave distal end surface.
 6. The apparatus of claim 1 wherein said tipcomprises a distal end surface having a plurality of depressions.
 7. Theapparatus of claim 1 wherein said tip comprises a body having markingsindicating the amount of the drug solution contained in the container.8. The apparatus of claim 1 further comprising a container whichcomprises: an outer wall; an inner wall; and an absorbent wick placedbetween said inner and outer wall, said wick absorbing any excess drugsolution that is not driven into the skin area through the formed pores.9. The apparatus of 8 wherein said wick comprises a spongy materialhaving highly absorbent and hydrophilic properties.
 10. The apparatus of8 wherein said wick comprises a highly absorbent and hydrophilicmaterial selected from the group consisting of absorbent cellulosematerial, polyvinyl alcohol sponge, sodium carboxy-methyl cellulose, andblotting paper.
 11. The apparatus of 8 wherein said inner wall comprisesfirst and second grooves, said tip comprises a body having first andsecond grooves and wherein said first and second grooves of the tip bodyare arranged opposite said first and second grooves of the containerinner wall, the arrangement defining first and second spaces foraccommodating first and second o-rings, respectively.
 12. The apparatusof 8 wherein said container further comprises an inlet septum forfilling said container with the solution.
 13. The apparatus of claim 8wherein said container is a cylinder.
 14. The apparatus of claim 8wherein said container comprises a transparent material.
 15. Theapparatus of claim 8 wherein said container comprises a plasticmaterial.
 16. The apparatus of claim 1 wherein said ultrasound frequencyis 20 KHz.
 17. The apparatus of claim 1 wherein said ultrasoundintensity is in the range of 5 W/cm² and 55 W/cm².
 18. The apparatus ofclaim 1 wherein said tip has a distal end located at a distance fromsaid skin area in the range of 1 millimeter to 10 millimeters.
 19. Theapparatus of claim 1 wherein said ultrasound radiation is continuous.20. The apparatus of claim 1 wherein said ultrasound radiation ispulsed.
 21. The apparatus of claim 1 wherein said period of time is inthe range of about 30 seconds to 5 minutes of continuous exposure tosaid ultrasound radiation.
 22. The apparatus of claim 1 wherein saidperiod of time is in the range of about 10 minutes to 20 minutes ofpulsed exposure to said ultrasound radiation with a 5% duty cycle. 23.The apparatus of claim 1 further comprising a container having an endcovered with a membrane at the skin area and containing said drugsolution, wherein said membrane is hydrophobic.
 24. A method ofperforming in-vivo sonoporation of a skin area and transdermal and/orintradermal delivery of a drug solution comprising: providing acontainer containing a predetermined amount of said drug solution;submerging a tip of an ultrasound horn in said drug solution throughsaid container; placing said container in contact with said skin area;and applying ultrasound radiation to said drug solution wherein saidultrasound radiation has a frequency in the range of 15 KHz and 1 MHzand is applied at an intensity, for a period of time and at a distancefrom said skin area effective to generate cavitation bubbles, whereinsaid cavitation bubbles collapse and transfer their energy into the skinarea thus causing the formation of pores in the skin area; and whereinsaid ultrasound radiation intensity and distance from the skin area arealso effective in generating ultrasonic jets, said ultrasonic jetsdriving said drug solution transdermally through said formed pores intothe skin area.
 25. The method of claim 24 wherein said tip is removablyconnected to said ultrasound horn comprising before submerging said tipin said drug solution attaching said tip to said ultrasound horn. 26.The method of claim 25 further comprising sterilizing said tip beforeattaching it to said ultrasound horn.
 27. The method of claim 24 whereinsaid tip comprises a flat distal end surface.
 28. The method of claim 24wherein said tip comprises a concave distal end surface.
 29. The methodof claim 24 wherein said tip comprises a distal end surface having aplurality of depressions.
 30. The method of claim 24 wherein said tipcomprises a body having markings indicating the amount of the drugsolution contained in the container.
 31. The method of claim 30 furthercomprising checking the amount of said drug solution contained in thecontainer before applying said ultrasound radiation.
 32. The method ofclaim 31 further comprising adding drug solution to said container. 33.The method of claim 24 wherein said container comprises: an outer wall;an inner wall; and an absorbent wick placed between said inner and outerwall, said wick absorbing any excess drug solution that is not driveninto the skin area through the formed pores.
 34. The method of claim 24wherein said ultrasound frequency is 20 KHz.
 35. The method of claim 24wherein said ultrasound intensity is in the range of 5 W/cm² and 55W/cm².
 36. The method of claim 24 wherein said tip has a distal endlocated at a distance from said skin area in the range of 1 millimeterto 10 millimeters.
 37. The method of claim 24 wherein said ultrasoundradiation is continuous.
 38. The method of claim 24 wherein saidultrasound radiation is pulsed.
 39. The method of claim 24 wherein saidperiod of time is in the range of about 30 seconds to 5 minutes ofcontinuous exposure to said ultrasound radiation.
 40. The method ofclaim 24 wherein said period of time is in the range of about 10 minutesto 20 minutes of pulsed exposure to said ultrasound radiation with a 5%duty cycle.
 41. The method of claim 24 wherein said formed pores have adiameter in the range of 1 micrometer to 100 micrometers.
 42. The methodof claim 24 wherein, said the container comprising a hydrophobicmembrane adjacent to the skin area.